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  • A similar circuit between pyramidal neurons and SST

    2024-02-04

    A similar circuit between pyramidal neurons and SST interneurons is also prevalent in layers 2/3 of the cortex. The synapses onto SST interneurons, however, are functionally weak, raising questions about their computational power. In the first set of experiments, Urban-Ciecko et al. (2018) show that pyramidal to SST neuron synaptic transmission fails up to 80% of the time both in brain slices in vitro and during the cortical downstate in vivo. They discovered, however, that carbachol, a cholinergic agonist, but not other neuromodulatory agonists, increases the strength of these pyramidal to SST synapses. Using a combination of bath-applied agonists and antagonists, they further demonstrate that nicotinic, but not muscarinic, receptors are involved in this enhancement. This carbachol-dependent synaptic strengthening has a presynaptic locus and is phenocopied by a PKA-activating drug, forskolin. Furthermore, the increase in pyramidal to SST neuron synaptic strength was blocked with a PKA inhibitor infused into the presynaptic pyramidal neuron, ruling out any network mechanisms. These observations are rather surprising because PKA-dependent modulation is not commonly associated with ionotropic receptors such as nicotinic receptors. Nevertheless, the results add to a handful of pioneering studies that observed nicotinic receptors creating slow and/or metabotropic dynamics. For instance, similar PKA-dependent potentiation of glutamatergic synapses through α7-containing nicotinic receptors has been described in the hippocampus (Cheng and Yakel, 2014). Interestingly, non-α7-containing nicotinic receptors can also produce an increase in pyramidal cell activity in cortex (Hedrick and Waters, 2015). Another fascinating study showed that cholinergic release can activate a subtype of cortical inhibitory neuron via unusually slow, non-α7 nicotinic receptors and in turn induce delayed disynaptic inhibition to neighboring cortical neurons (Arroyo et al., 2012). Common to these studies are the surprisingly slow actions of nicotinic receptor mechanisms consistent with the involvement of metabotropic pathways. Until recently, evaluating the temporal dynamics of cholinergic effects has been hindered by the paucity of alternatives to the bath application of retinoic acid receptor agonists and antagonists. Although effective (e.g., Chen et al., 2015), this pharmacological approach has led to somewhat confusing observations regarding which neuronal populations acetylcholine modulates and what effect it has on each (for review, see Muñoz and Rudy, 2014). The advent of optogenetic and transgenic techniques has enabled the field to investigate with temporal precision and circuit specificity the effects of acetylcholine release. Urban-Ciecko et al. (2018) asked whether optogenetically induced acetylcholine release can produce a rapid enhancement of the pyramidal to SST synapse. To precisely control the timing of acetylcholine release, they expressed channelrhodopsin in basal forebrain cholinergic neurons and delivered brief (10 ms) light flashes. They show that a single and rather brief pulse of endogenous acetylcholine is sufficient to reproduce the effects of bath-applied cholinergic agonists. Intriguingly, the synaptic potentiation is temporally restricted and peaks about 200 ms after acetylcholine delivery, a relatively long delay but comparable to those reported by the previous studies discussed above. What are the consequences of this delayed cholinergic boosting of pyramidal-SST synapses? To address this question, we need to consider the dynamics of the circuit in which the pyramidal-SST motif is embedded. Recall that SST neurons tend to inhibit the distal dendrites of pyramidal cells, precisely where top-down, long-range inputs arrive. SST neurons, in turn, are inhibited by VIP-expressing neurons, specializing in disinhibition (Kepecs and Fishell, 2014). Phasic cholinergic activity can recruit disinhibition either through inhibitory neurons in layer 1 (Letzkus et al., 2011) or likely through VIP neurons in layers 2/3 (although this has not yet been directly demonstrated; Figure 1). Hence, acetylcholine-mediated disinhibition could open a gate for long-range feedback to influence pyramidal neuron activity. In the ensuing time window of pyramidal disinhibition, local and long-range cortical inputs would be integrated into the output of pyramidal cells. Then, the window would be closed shut by feedback inhibition due to the delayed enhancement of pyramidal-SST neuron synapses described in this study. The same burst of acetylcholine could thereby drive both the opening and the closing of a brief plasticity window: pyramidal cell disinhibition acting immediately and feedback inhibition occurring after some time delay. This disinhibition/feedback inhibition balance could therefore create a temporal frame for associative plasticity in cortex (Figure 1).